Physiologically-active base.



HEINRICH HOERLEIN, 0F VOHWINKEL, GERMANY, ASSIGNOR TO SYNTHETIC JPATEN'RS 60., INC., 01? NEW YORK, N. Y., A CORPORATION OF NEW YORK.

PHYSIOLOGICALLY-ACTIVE BASE.

Ito Drawing.

able properties as a substitute for ergot, or

secale preparations; and it comprises a preparation of p-oxyphenylethylamin and betaimidazolylethylamin made by combining these two bases in an isolated condition or in the form of their salts or by producing them simultaneously or otherwise, the preparation being in the form of a mixture of the two bases in powder form or of tablets or pills or "of aqueous solutions of their salts, etc., all as more fully hereinafter set forth and as claimed.

It is known that preparations of ergot, or

secale cornutum, as well as various substances or bases isolated therefrom, have a physiological effect upon the uterus and upon the blood vessels, causing their contraction; but the administration of these preparations shows certain disadvantages. Preparations made from ergot or secale cornutum usually contain more or less inert constituents as well as constituents antagonistic to each other in their action. The isolated bases referred to have-been experimented with as substitutes for secale preparations but their use in the pure state is accompanied by such after effects as to often render them objectionable. The beta-imidazolylethylamin when employed in therapeutical doses, frequently causes headache, congestion of the head, erythema'over the body and limbs, formication in the arms and legs, nausea, irritation of the conjunctiva, palpitation of the heart, and even marked cyanosis in consequence of temporary arrest of respiration, convulsions and loss of consciousness'(Jaeger Oentmlblwtt fdr Gym/flaw logic 1913 No. 8; Kehrer, Mue'nch. Med. Woche'nschrift, No. 33, 1912). The p-oxyphenylethylamin has the great disadvantage of acting only upon the impregnated and puerperal uterus, but not upon the virginal. or quiescent uterus. The physiological efi'ect of both these bases is partly antagonistic and partly synergistic. The beta-imidazolyl- Specification of Letters Patent.

Patented Dec. 2e, laid.

Application filed July 22, 1913. Serial No. 780,461.

ethylamin acts as a poison upon the autonomic nervous system. It produces convulsions of the bronchial and visceral musculature, inhibition of the cardiac action, relaxation of the abdominal vessels, reduction of blood pressure (in cats and humans), fall of temperature, and a tetanizing effect upon the uterus. The last named action .is supported by the direct influence of the beta-imidaztlylethylamin upon the .unstriped musculature itself, as can be demonstrated on the isolated organ, the uterine contraction being independent of the state in which the uterus may be. On the other hand, p-oxyphenylethylamin has a toxic effect upon the sympathetic nerves It causes dilation of, the pupils and the bronchi, constriction of the blood vessels, increase of blood pressure, and contraction of the pregnant or puerperal uterus, but not of the virginal or quiescent uterus. Its action upon this organ is like that of a stimulation ofthe hypogastric nerve.

The remarkable. discovery has now been made that by combining both bases, the disagreeable after-effects of the beta-imidazolylethylamin can be greatly diminished or completely neutralized, while the valuable properties of both bases supplement each other, or in the sense of Burgis law intensify each other, so that a preparation made from these two bases forms a valuable and in many respects superior substitute for secale cornutum or its extracts. This preparation is moreover free from the numerous other substances always present in ergot and whichas is kiiown in the case of opium, digitalis and other vegetable drugsmaterially influence the complex action of the natural remedy. The preparation of these two bases, being free from all inert matter and objectionable constituents of the plant, is capable of exact dosage. I

The preparation of the present invention acts both upon the virginal and quiescent uterus as well as upon the pregnant and puerperal uterus. This action appears all the more remarkable since, as is well known, the para-oxyphenylethylamin fails to exert any efl'ect upon the virginal and quiescent uterus, and may, indeed, have a relaxing effect, so that in the preparation of both bases an impairment of the contractile action of the beta-imidazolylethylamin was to be feared.

present invention may be made in various ways and may exist in various conditions. The two bases may be used in the isolated state in appropriate mixtures, or the bases may be crystallized together in the desired proportions; or salts of the bases may be prepared either separately or in joint crystallization or in aqueous solution.

The bases themselves may be recovered from preparations of ergot or secale cornutum or they may be prepared from histidin and tyrosin by putrefactive fermentation. By subjecting a mixture of histidin and tyrosin to putrefactive fermentation the bases are jointly produced in an economical manner and if desired need not be separated from each other for further use.

The preparations of poxyphenylethylamin and beta-imidazolylethylamin of the present invention are intended to be used as substitutes for ergot or secale cornutum, over which. however, they possess very material advantages as already pointed out. The proportions of the two bases which have been found to give the desired physiological action are about 1 part of beta-imidazolylethylamin to +1 to 30 parts of p-oxyphenyL ethylamin. Thus an aqueous solution may be prepared by using 0.1-0.5 parts of betaimidazolylethylamin-hydrochlorid and 2-3 parts of p-oxyphenylethylamin-hydrochlorid dissolved in 1,000 parts of water.

The preparation of the two bases indicated above in the proportions of 1 partto 4 parts is a white powder which shows the alkaloidal reaction, 2'. 0., gives a precipitate with picric acid and bichlorid of mercury, furnishes azo bodies with diazo compounds, and is very easily soluble in water. Among the salts of the two bases those of greatest importance are the ones most easily soluble in water. From the hydrochlorids the free bases may be prepared as follows: 1 part of betaimidazolylethylamin-hydrochlorid and 1 parts of p-oxyphenylethylamin-hydrochlorid are suspended in boiling alcohol and treated while stirring with the calculated amount of sodium ethylate. The separated salt is'filtered off and the alcoholic solution of the free bases is neutralized by means of phosphoric acid. After evaporation to dryness, the residue can be used either in the powder form or in the form of tablets or pills, or can be made up into solutions of the desired strength.

The bases may be prepared by subjecting mixture of histidin and tyrosin to put-reactive fermentation, as already described, and the resulting product or preparation of the two bases may be used in medicine as described above.

An elixir may be made by dissolving parts of beta -imidazolylethylamin -l1ydrochlorid and 2 parts of p-oxyphenylethylaminhydrochlorid in 1,000 parts of water. In stead of using the pure salts of the two bases, the fermentation products of histidin and tyrosin can be used and their hydrochlorids dissolved in water.

The composition of the present invention can be administered by subcutaneous, intravenous, intramuscular, per oral or rectal application. The dose may be, for example, one-fourth to one-half mg. beta-imidaz0lylethylamin salt and 2 to 3 mg. of the p-oxyphenylethylamin salt.

In the foregoing description and in the accompanying claims the term preparation of the two bases is used as generic to preparations made from the isolated bases or their isolated salts as well as to preparations containing the two bases jointly crystallized or otherwise jointly combined during their process of preparation, as by fermentation, and whether these preparations are in a powder or tablet or other solid form or in the form of aqueous solutions, etc. The terms p oxyphenylethylamin substances and beta -imidazolylethylamin substances are similarly used in a generic sense to include both the free bases and their salts, etc.

I claim:

1. As a new medicinal composition a mixture comprising p-oxyphenylethylamin substances and beta-imidazolylethylamin substances characterized by showing the alkaloidal reactionand giving azo bodies with dia zo compounds;

2. As a new medicinal composition a mixture comprising salts of p-oxyphenylethylamin and beta-imidazolylethylamin, characterized by showing the alkaloidal reaction.

3. As a new medicinal composition a physiologically active preparation of the salts of the two bases p-oxy-phenylethylamin and beta-imidazolylethylamin in the proportions of about 1 part of the beta-imidazolylethylamin-hydrochlorid and 4 parts of the p-oxyphenylethylamin-hydrochlorid.

4 As a new medicinal composition a physiologically active preparation of the two bases p-oxyphenylethylamin and betaimidazolyethylamin in the proportions of about 1 part of p-oxyphenylethylamin to 4 parts of beta-imidazolylamin, said preparation being in the form of water-soluble salts of the two bases.

In testimony whereof I have hereunto set my hand in the presence of two subscribing witnesses.

HEINRICH HOERLEIN. [L. 8.]

Witnesses:

HELEN NUFER, ALBERT Nurse. 

